Treating Persistent Hyperglycemia in Patients with Type 2 Diabetes Mellitus

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton and welcome to the AACE Clinical Conversations. In this program, we will discuss the treatment of persistent hyperglycemia in patients with type 2 diabetes mellitus.

Joining me today is Dr. Philip Orlander, the Professor and Director of the Division of Endocrinology, Diabetes and Metabolism at the University of Texas Medical School at Houston.

Also with us is Dr. Dale Hamilton, attending physician with the Methodist Academic Associates and Diabetes Clinical Service Chief at the Methodist Hospital in Houston. Thanks to both of you for joining us.

We all know that our patients with diabetes that we see who are new diabetics respond well to treatment initially but in a fairly short period of time, their blood sugars go back up, or by the time that we see them, if they have been referred to us, patients have hyperglycemia again.

Dale, tell us a little bit about the experience with response to treatment and recurrence of hyperglycemia in these patients.

DALE J. HAMILTON, MD, FACE: The experience, in my case, and in the case of most endocrinologists and physicians that treat diabetes is that initial therapy fails. There is a lack of, to use a current term, durability in persistence of glucose control in patients taking oral medicines.

The initial treatment is usually that of a lifestyle and dietary recommendation for patients with type 2 diabetes followed by the prescription for an oral medicine, usually a single agent, and monotherapy is begun. And it often fails.

It then requires either the addition of a second oral medicine or the addition of insulin. It's a strong body of evidence that has accumulated beginning with the UKPDS trial published in 1989 that reports the lack of efficacy in the long run when you're treating patients with either lifestyle changes or monotherapy.

In the UKPDS trial, which was conducted, by the way, from 1977 to 1991, a time when only two of the current five or six classes of agents were available to us, and the insulin that was limited to NPH and regular, showed that within three years, 50% of the patients failed and required the addition of either a second oral medicine or the addition of insulin. Within nine years, 25% of the patients had failed.

These results have been supported by other studies, and most recently the so-called ADOPT trial published in the New England Journal of Medicine in December showed that failure of oral medicines within four or five years was comparable to that in UKPDS.

CARLOS R. HAMILTON, JR., MD, FACE: Yes. This particular study suggested that there were some differences in the durability of various first line agents. Has that been something that you think should influence our choice of these drugs?

DALE J. HAMILTON, MD, FACE: Yes. That is true. One of the primary outcomes was to compare a thiazolidinedione, rosiglitazone, to a sulfonylurea and metformin therapy. It showed that the failure rate was significantly less with rosiglitazone.

One then should keep that in mind, understanding that type 2 diabetes is a progressive disease, one in which the ability to make insulin diminishes over time, and there is a possibility that medicines in the class of thiazolidinediones or rosiglitazone might slow that loss of beta cell function.

CARLOS R. HAMILTON, JR., MD, FACE: But this is a part of a natural progression, a natural history, if you will, of diabetes. It doesn't necessarily mean that something hasn't gone the way you'd expected because this is what you'd expect.

Philip, what is your response to this situation in your patients? What do you do when patients fail to respond to the initial therapy that they may be on?

PHILIP R. ORLANDER, MD: Well, I think one of the problems that we've seen across the practices of many people is the delay in terms of starting therapy in the first place, adding additional therapy and then going to insulin, and so there is a period of years before the patient is started on effective therapy.

I think that the editorials recently by David Nathan regarding how to proceed on this are very to the point, and his suggestion that once you have made the diagnosis of diabetes, that immediate drug therapy should be started, rather than giving a prolonged trial of diet and exercise.

From that consensus, metformin was chosen as a good choice as a first line agent. From there, as the blood sugar is not in optimal range, then there is a choice between several different medications, and they vary from the most effective being insulin to probably the least expensive being sulfonylureas to agents such as the thiazolidinediones, which as mentioned by Dale, have some other both pros and cons in terms of being more expensive, but having some durability and efficacy advantages.

From there, the question is where to go. Should the patient did then go to insulin if they fail those agents? Most likely we would stop the sulfonylurea at that point if insulin was added, and then looking at some of the newer agents in terms of some added benefit in selected cases.

CARLOS R. HAMILTON, JR., MD, FACE: With these new agents, many of us have found that sulfonylureas may have a more limited role in the management of patients than we had used in the past when this was basically the only drug available, or certainly one of the only two available. Is this your experience, that sulfonylureas are probably not as effective or as user-friendly, if you will?

PHILIP R. ORLANDER, MD: It's always hard to generalize with such a heterogenous group of diseases as type 2 diabetes. Certainly, in patients who appear more insulin resistant, the agents such as thiazolidinediones or metformin seem to be more effective.

In patients who look like they're starting to fail in terms of beta cell secretion, then sulfonylureas are very effective, at least for a short period of time, and again, they're quite inexpensive. So that gives you a couple of years, but the durability, as you mentioned, is limited, at which point usually the decision is made to go to some form of insulin therapy, be it injected, short-acting, long-acting, inhaled.

And again, I think that's one of the spots where people hesitate to move and that puts the patient at a higher risk for a longer period of time of hyperglycemia.

CARLOS R. HAMILTON, JR., MD, FACE: Well, this is one of the issues that comes up, is that many of the referring physicians or family practice physicians in the communities are reluctant to start patients on insulin. Dale, what is your experience with timing of the use of insulin? At what point should we go to insulin when other things are not doing as well as we expect?

DALE J. HAMILTON, MD, FACE: That's a very important question, and it's one that needs to be addressed by the endocrine community. Increasingly now, we are using insulin earlier and earlier, now that we understand that type 2 diabetes is a progressive disease, one in which endogenous insulin secretion diminishes over time. We now tend to add insulin to oral therapy or use insulin alone at an earlier stage in patients.

In our practice, we look at the fasting blood glucose and the hemoglobin-A1c, in particular. When we begin to lose control of either one or both of those, then we will implement insulin, usually as an add-on to the oral medicine.

We will consider insulin when the A1c begins to rise above 8 or the fasting blood glucose is in excess of 140.

The recent American Diabetes Association recommendations for treatment of diabetes actually considers greater than 180, but we found in our practice that we're more aggressive than that, and we'll add insulin earlier and combine it with oral medicines.

CARLOS R. HAMILTON, JR., MD, FACE: So there are many others that feel that if the hemoglobin-A1c is 8.5 or greater and you're on oral agents, that is simply a time when you're not going to get any better with the oral agents, and it's time to add insulin or some other drug. How do you start insulin in these patients? Do you give it the bedtime types of insulin, or...

DALE J. HAMILTON, MD, FACE: Yes. We start it in one of two ways. We either add NPH, an immediate-acting insulin at bedtime and ask the patient to monitor that fasting blood glucose. So, for example, we might start at 10 units at bedtime, and ask them to adjust that up every three days, until we have a fasting blood glucose less than 120.

Alternatively, we'll use the insulin glargine taken usually in the morning, again, looking at the next morning's fasting blood glucose in advance that until we have control of the fasting blood glucose.

CARLOS R. HAMILTON, JR., MD, FACE: How high might you go with that long-acting insulin like that in the once-a-day dose in a non-insulin dependent diabetic like this as a single injection?

DALE J. HAMILTON, MD, FACE: We will raise it enough to control the blood glucose. With insulin glargine, when we get to doses of 80 or 90 units per day, then we begin to divide it. But we have many patients taking 400 and 500 units a day so that we will advance it until we have control of the blood glucose.

CARLOS R. HAMILTON, JR., MD, FACE: That's interesting. There are some of us that feel that when you get above about 40 units of long-acting insulin like Lantus and you're still not getting where you want to go, it's time to go to multiple daily injections or perhaps some other approach.

What about the use of insulin in these patients Philip? How do you use...

PHILIP R. ORLANDER, MD: Well, one of the concerns, of course, is that as you drive up the insulin dose, the weight typically goes up as well. And that's a major concern for the patients, and frequently they just increase their intake so that the blood sugars don't change a whole lot, and now they're much heavier and less happy.

In addition, they may be having, if they're on multiple doses of different kinds of insulin, they may be having hypoglycemia at various times during the day, and that again causes them to increase their weight.

Many of these patients are quite insulin resistant and we need to go to a concentrated insulin, such as U-500 for the very reason that you just mentioned, that the less concentrated insulins become less effective at higher doses.

Alternatively, we start to add other of the new agents. Now, pramlintide is indicated in use with insulin, and we use it in two different circumstances based on the type of diabetes, so for patients with type 1 diabetes, if we find that we can't control the postprandial blood sugars or we're having unacceptable late hypoglycemia because of dosing of the fast-acting insulin, then pramlintide may be very helpful.

It will cause some drop in appetite. It will cause an improvement in postprandial blood sugars. There is an increased risk of hypoglycemia and there is an increased risk of nausea and vomiting. So it requires a very attentive endocrinologist and a very knowledgeable patient to be able to mix those two, but we have had good success in both controlling weight gain, as well as controlling blood sugar in patients with type 1 diabetes.

In the patients with type 2 diabetes, the weight becomes much more of an issue. So we keep on raising the insulin, and the patient's weight keeps on going up. They continue to have high blood sugars after meals because the insulin really can't get in there fast enough for that.

CARLOS R. HAMILTON, JR., MD, FACE: So the use of pramlintide along with insulin in these type 2 patients is an effective strategy, you think?

PHILIP R. ORLANDER, MD: Yes. It allows us sometimes to get away from using pre-meal insulin in some of these obese patients. So they may be able to do well on a long-acting background insulin and then just give pramlintide pre-meal, which in a sense is the same thing in terms of number of injections as giving pre-meal insulin.

We also use pramlintide in patients with type 2 diabetes who are not on insulin, again for the same reasons. Although if I had that choice, I would probably go to exenatide, which has a better weight reduction profile and otherwise controls postprandial blood sugars somewhat better.

CARLOS R. HAMILTON, JR., MD, FACE: So there certainly are some other strategies that can be used along either with insulin or without insulin in these type 2 patients.

Dale, of course, the new drug on the block is the DPP-4 class of drugs. Have you had experience with that, and where do you feel that fits into this group?

DALE J. HAMILTON, MD, FACE: Yes, we have experience with this new class of medicines. The role of these agents though in the treatment of diabetes is yet to be defined. We clearly do not understand yet what the effective use of these agents will be, and we have not identified the complications of it.

But we find them particularly helpful in older patients, say patients older than 60 or 70 in whom there is a risk of hypoglycemia.

Many of these patients have chronic kidney disease with elevations of the serum creatinine in the range of 1.5 or 2 that would make treatment with sulfonylureas dangerous. It would increase the risk of hypoglycemia.

Metformin, on the other hand, is contraindicated in that case, so the DPP-4 inhibitors then might be useful in this circumstance.

CARLOS R. HAMILTON, JR., MD, FACE: So there's certainly a lot of options that our patients can use in terms of trying to control their blood sugar when the initial and subsequent treatments cease to be as effective.

Well, that's really been very helpful and very useful information I hope. And I just want to thank you both for being with us today. And again, I'm Dr. Carlos Hamilton, and thank all of you for watching.